SU608471A3 - Method of preparing a-methyl-3,4-dioxyphenylalanine derivatives or salts thereof - Google Patents
Method of preparing a-methyl-3,4-dioxyphenylalanine derivatives or salts thereofInfo
- Publication number
- SU608471A3 SU608471A3 SU742063140A SU2063140A SU608471A3 SU 608471 A3 SU608471 A3 SU 608471A3 SU 742063140 A SU742063140 A SU 742063140A SU 2063140 A SU2063140 A SU 2063140A SU 608471 A3 SU608471 A3 SU 608471A3
- Authority
- SU
- USSR - Soviet Union
- Prior art keywords
- hours
- dihydroxyphenyl
- solution
- mixture
- hydrochloride
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims description 6
- 238000000034 method Methods 0.000 title description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- -1 ethyl-phenyl Chemical group 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 9
- 239000012153 distilled water Substances 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 6
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003729 cation exchange resin Substances 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims 8
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 claims 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 4
- 239000003957 anion exchange resin Substances 0.000 claims 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 3
- 239000012346 acetyl chloride Substances 0.000 claims 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 238000001953 recrystallisation Methods 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 2
- LELWHPFBIHGMGF-UHFFFAOYSA-N 1-(1-chloroethyl)pyrrole-2,5-dione Chemical compound CC(Cl)N1C(=O)C=CC1=O LELWHPFBIHGMGF-UHFFFAOYSA-N 0.000 claims 1
- AZVYYSCOCHRFKW-UHFFFAOYSA-N 1-(hydroxymethyl)pyrrolidine-2,5-dione Chemical compound OCN1C(=O)CCC1=O AZVYYSCOCHRFKW-UHFFFAOYSA-N 0.000 claims 1
- KZCSJWFLPQFDNW-UHFFFAOYSA-N 1-ethenylpyrrole-2,5-dione Chemical compound C=CN1C(=O)C=CC1=O KZCSJWFLPQFDNW-UHFFFAOYSA-N 0.000 claims 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 239000005909 Kieselgur Substances 0.000 claims 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims 1
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000006286 aqueous extract Substances 0.000 claims 1
- 239000012298 atmosphere Substances 0.000 claims 1
- 229910052793 cadmium Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000004821 distillation Methods 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- 239000012362 glacial acetic acid Substances 0.000 claims 1
- 238000011835 investigation Methods 0.000 claims 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims 1
- 239000011592 zinc chloride Substances 0.000 claims 1
- 235000005074 zinc chloride Nutrition 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229940035423 ethyl ether Drugs 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WBBPRCNXBQTYLF-UHFFFAOYSA-N 2-methylthioethanol Chemical compound CSCCO WBBPRCNXBQTYLF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241001585714 Nola Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- IJSORYCHINCABL-UHFFFAOYSA-N n-[2-(2-acetamidoethoxy)ethyl]acetamide Chemical compound CC(=O)NCCOCCNC(C)=O IJSORYCHINCABL-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
ных атома и 1 гетероатом, которым вл етс азот, или Bj-xa X - кислород , сера или группа NH, В - алкил С| - С5ИЛИ ацильный радикал органической ациклической карбоновой кислоты с C;j- Cg, заключающийс в том, что соединение общей формулыatom and 1 heteroatom, which is nitrogen, or Bj-xa X - oxygen, sulfur or group NH, B - alkyl C | - C5IL or acyl radical of an organic acyclic carboxylic acid with C; j-Cg, consisting in that a compound of the general formula
где 3 -СООН, СО-галоген, или соль карбоновой кислоты, этерифицируют с помощью соединени формулы:where 3-COOH, CO-halogen, or a carboxylic acid salt, is esterified with a compound of the formula:
1one
(Ш),(Ø),
TZjTzj
где , щелочной металл-0, галоген или замещенна SOj-rpynna, art, т, В|, EJJ и EJg имеют вышеуказанные значени Процесс этерификации провод т в обычных услови х.where alkali metal-0, halogen or substituted SOj-rpynna, art, t, B |, EJJ and EJg are as defined above. The esterification process is carried out under ordinary conditions.
Целевые сложные эфиры преимущественно в виде 1 -изомеров выдел ют р свободном виде или в виде солей. Дл образовани солей примен ют такие кислоты как сол на , щавелева , малеинова .The desired esters, preferably in the form of 1 -isomers, are isolated in free form or in the form of salts. For the formation of salts, acids such as hydrochloric, oxalic, maleic are used.
Пример. Получение гидрохло рида 2-ацетамидоэтиг- Ь .-3-(3,4-диидроксифенил )-2-метилаланината.Example. Preparation of hydrochloride with 2-acetamido-ethigb.-3- (3,4-dihydroxyphenyl) -2-methylalaninate.
Суспензию 88,3 г (0,30 мол ) U -3 (3,4-дигидроксифенил)-2-метилаланин гидрохлорида в виде этанольного сольата , полученного при выпаривании эта- , нольного раствора гидрохлорида при пониженном давлении и 146,4 г (1,42 мол ) N -ацетил9таноламина, наход щуюс под атмосферой азота, нагревают до темпеатуры 104-108 С. Добавл ют 8,48 г (0,713 мол ) хлористого тионила, ввоимого в реакционную смесь при перемеивании в течение 15 мин. Процесс сопровождаетс интенсивным вспениванием реакционной смеси. После.того, как введение хлористого тионила закончено, реакционную смесь перемешивают при температуре 104-108 с в течение 18час. Затем в течение семи минут ввод т дополнительно .г . (0,357 мол ) хлористого тионила ;-1Реакционную смесь перемешивают при твмпера :урё. 104-108 С еще в течение. 3,.5.чаСрв -.;-а. охаждают до 3 О с. и выпаривают при пониженном давлении, получают .в зкий масл нистый продукт, Его суспендируют в 100 мл хлороформа, а хлороформ выпаривают при пониженном давлении. Эту процедуру повтор ют трижды,.а затем масло промывают 100 мл бензола, который декантируют после промывки. Полученный остаток раствор ют в 700 млA suspension of 88.3 g (0.30 mol) of U-3 (3,4-dihydroxyphenyl) -2-methylalanine hydrochloride in the form of an ethanol solate, obtained by evaporation of ethanol and a hydrochloride solution under reduced pressure and 146.4 g (1 , 42 mol) N-acetyl9thanolamine, under a nitrogen atmosphere, is heated to a temperature of 104-108 ° C. 8.48 g (0.713 mol) of thionyl chloride, added to the reaction mixture with stirring for 15 minutes, is added. The process is accompanied by intensive foaming of the reaction mixture. After the introduction of thionyl chloride is complete, the reaction mixture is stirred at 104-108 seconds for 18 hours. Then within seven minutes, an additional yr is added. (0.357 mol) of thionyl chloride; -1 The reaction mixture is stirred at tvmpera: ur. 104-108 C for more. 3, .5.chSrv -.; - a. cool down to 3 o. and evaporated under reduced pressure, a viscous oily product is obtained, It is suspended in 100 ml of chloroform, and chloroform is evaporated under reduced pressure. This procedure is repeated three times, and then the oil is washed with 100 ml of benzene, which is decanted after washing. The residue obtained is dissolved in 700 ml.
изопропанола и добавл ют б л этилового эфира. Образующийс осадок промывают 500 мл этилового эфира и встр хивают в 6 л смеси, состо щей из 10% этанола 5 и 90% этилацетата (по объему), 150 мл насыщенного раствора карбоната натри и 100 г кристаллического карбоната натри . Органический экстракт сушат над безводным сульфатом магни , фильтQ руют и выпаривают при пониженном давлении , получают свободное основание ацетамидоэтилового эфира. Основание обрабатывают 15 г фумаровой кислоты, растворенной в 300 мл изопропанола, фумарат высаждают добавлением необходимого дл этого количества этилового эфира. Фумарат еще раз переосаждают из изопропанола добавлением необходимого дл этого количества этилового эфира, а затем перевод т его обратноisopropanol and add lb of ethyl ether. The resulting precipitate is washed with 500 ml of ethyl ether and shaken in 6 liters of a mixture consisting of 10% ethanol 5 and 90% ethyl acetate (by volume), 150 ml of a saturated solution of sodium carbonate and 100 g of crystalline sodium carbonate. The organic extract is dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the free base of acetamidoethyl ether. The base is treated with 15 g of fumaric acid, dissolved in 300 ml of isopropanol, and the fumarate is precipitated by adding the required amount of ethyl ether for this. Fumarate is again reprecipitated from isopropanol by adding the required amount of ethyl ether, and then converting it back
в свободное: основание обработкой 200млin free: base treatment 200ml
смеси 10% этанола и 90% этилацетата (по объему), 20 мл .насыщенного раст-. вора карбоната натри и 20 г кристаллического карбоната натри . При растворении свободного основани в 100 мл абсолютного этанола и добавл ют 10 мл 9,6 н, нес , образуетс гидрохлорид, его высаживают добавлением 1 л этилового эфира. После-трехкратного пере0 осагкдени из этанола-этиловьам эфиром получают 15,1 г (15%) гидрохлори.5а 2-ацетамидоэтш1- L -3-(3,4-дигидроксифенил ) -2-мeтилaJIaнинaтa, S| 0,57 (тонкослойна хроматографи на силикагеле,mixtures of 10% ethanol and 90% ethyl acetate (by volume), 20 ml of saturated plant. sodium carbonate thief and 20 g of crystalline sodium carbonate. When the free base is dissolved in 100 ml of absolute ethanol and 10 ml of 9.6 n is added, carried, hydrochloride is formed, and it is planted by adding 1 l of ethyl ether. After three times pereoscans from ethanol-ethyl ether, 15.1 g (15%) of hydrochloride 5a 2-acetamidoethyl-1-L-3- (3,4-dihydroxyphenyl) -2-methyl-1HIaninate, S | 0.57 (thin layer chromatography on silica gel,
5 смесь метанол:бензол 1:1).5 methanol: benzene 1: 1).
Найдено,%: С 50,49; Н 6,69; N 8,49 Ci4H2oMaO.-HCeFound,%: C 50.49; H 6.69; N 8.49 Ci4H2oMaO.-HCe
Вычислено,%: С 40,52; Н 6,36; К В,41. 0 т.пл. 125-130 с (разл.).Calculated,%: C 40.52; H 6.36; K B, 41. 0 m.p. 125-130 s (decomp.).
П р и м е р 2. Получение гидрата кислого оксалата-3-ацетамидопропил- d. -3-(3,4-дигидроксифенил)-2-метилаланината .PRI mme R 2. Preparation of hydrate of acid oxalate-3-acetamidopropyl- d. -3- (3,4-dihydroxyphenyl) -2-methylalaninate.
5 К 250 г полуторного гидрата Ь -3- (3,4-дигидроксифенил)-2-метилаланина при 25- С добавл ют 275 мл хлористого тионила и смесь нагревают на паровой бане. После прогревани в течение двух 0 часов концентрированн5ло реакционную смесь разбавл ют 7,5 мл диметилформамида/ растворенно.го в 25 мл бензола, и перемешивают на вод ной бане до полного прекращени га-зовыделени . Добавл ют 100 гш бензола, сложный эфир сернистой, кислоты отфильтровывают, промывают 100 мл бензола, 100 мл хлороформа и 100 мл эфира/ сушат при пониженном давлении, в результате чего получают 280 г промежуточного сложного эфира сернистой кислоты, т.пл, 199°C (разл.).5 To 272 ml of thionyl chloride are added to 250 g of a half-hydrate of b-3- (3,4-dihydroxyphenyl) -2-methylalanine at 25 ° C and the mixture is heated on a steam bath. After heating for two hours, the concentrated reaction mixture is diluted with 7.5 ml of dimethylformamide / dissolved in 25 ml of benzene and stirred in a water bath until all gas evolution ceases. 100 gs benzene is added, the sulfurous acid ester is filtered off, washed with 100 ml of benzene, 100 ml of chloroform and 100 ml of ether / dried under reduced pressure, giving 280 g of sulfuric acid intermediate ester, mp, 199 ° C (different).
Смесь 13,7 г сырого промежуточного эфира сернистой кислоты, 24,98 г (0,212 мол ) N -ацетилпропаноламина 5 и 2 г безводного диметилформамида перемешивают на вод ной бане в течениеосадок промывают 3 раза по 250 мл сме20 час, а затем охлаждают. Реакцией-си, 20% этанола и 80% этилацетата ную смесь промывают шесть раз по 200мл (по объему), соедин ют с первым этаэтилового эфира, четыре раза по 20амлнол-этилацетатным экстрактом и осухлористым метиленом и высушивают при 5 ™ают над безводным сульфатом магни , пониженном давлении. Оставшийс полу-Фильтруют,.растворитель отгон ют при кристаллический материал перемешиваютпониженном давлении, а остаток дел т с 200 мл смеси, состо щей из 20% эта-хроматографически на селикагеле. нола и 30% этилацетата (по объему), 2,3 г продукта разбавл ют смесью 20 мл насыщенного раствора карбоната JQ метанол:хлороформ 1:3, добавл ют растнатри и 20 г кристаллического карбо-вор 1,3г щавелевой кислоты в 5 мл ната натри . Органический слой осуша-этанола, переосаждают этиловым эфиром, ют над безводньгм сульфатом магни , от-После трехкратного переосаждени профильтровывают и фильтрат добавл ют кдукт промывают в этаноле, высаживают раствору 3,2 г щавелевой кислоты,этиловым эфиром. Получают 300 мг кисрастворенной в 50 мл этанола. Раст-лого оксалата 2-метилтиоэтил- Ь -3воритель отгон ют при пониженном дав--(3,4-дигидроксифенил)-2-метилаланилении , а конечный продукт переосажда- .ната, х юматографически однороден се- ют растворением в 50 мл этавола и до-ликагель, смесь метанол:хлороформ 1:1:5, бавлением 500 мл этилового эфира. Про-н. 0,83, т.пл. 85-90с (разл J . дукт вновь переосаждают растворением . Найдено,%: С 48,00; Н 6,10; N 4,07 его в 50 мл этанола и добавлением . ).2 z 4500 мл этилацетата, в результате Вычислено,%: С 47,99; Н 5,64; N3,73. получают гидрат кислого оксалата 3-ацетамидопропил- L -3-(3,4-дигидрок- П р и м е р 4. Получение гидрохлосифенил )-2-метилаланината, К.0,5 (тон 5РИДа пивалоилоксиметила- L -3-{3,4кослойна хроматографи на селикагеле,-дигидроксифенил)-2-метилаланината. :смесь метанол:хлороформ (1:3). . Раствор 0,95 г (4,0 мол ) L -3Найдено ,%: С 48,73; Н 6,85; Мб,68- (3,4-дигидроксифенил)-2-метилаланинаA mixture of 13.7 g of crude sulfuric acid intermediate ester, 24.98 g (0.212 mol) of N-acetylpropanolamine 5 and 2 g of anhydrous dimethylformamide is stirred on a water bath for 6 times, washed with a mixture of 3 times 250 ml of an hour and then cooled. Reaction-si, 20% ethanol and 80% ethyl acetate mixture is washed six times with 200 ml (by volume), combined with the first ethylether, four times with 20 ml of ethyl acetate and methylene chloride and dried at 5 ™ ate over anhydrous magnesium sulphate , reduced pressure. The remaining semi-filtered, the solvent is distilled off under a crystalline material, is stirred under reduced pressure, and the residue is divided with 200 ml of a mixture consisting of 20% of this chromatography on silica gel. nola and 30% ethyl acetate (by volume), 2.3 g of the product is diluted with a mixture of 20 ml of a saturated solution of carbonate JQ methanol: chloroform 1: 3, sodium carbonate and 20 g of crystalline carbide of 1.3 g oxalic acid in 5 ml of nat is added on three . The organic layer was dried-ethanol, reprecipitated with ethyl ether, over anhydrous magnesium sulphate, filtered off from three-times re-precipitation, and the filtrate was added and washed with ethanol, precipitated with a solution of 3.2 g of oxalic acid, and ethyl ether. 300 mg of oily solution in 50 ml of ethanol are obtained. 2-methylthioethyl-L-3 solvent, a solid oxalate, is distilled off under reduced pressure — (3,4-dihydroxyphenyl) -2-methyl-alanilation, and the final pre-precipitate, x homographically, dissolves in 50 ml of ethavol and before the mixture, the mixture is methanol: chloroform 1: 1: 5, by suppression of 500 ml of ethyl ether. Pro-n. 0.83, m.p. 85-90s (dec. J. Duck is again replanted by dissolving. Found,%: 48.00; H 6.10; N 4.07 in 50 ml of ethanol and addition.). 2 z 4500 ml of ethyl acetate, as a result %: C, 47.99; H 5.64; N3.73. 3-acetamidopropyl-L-3- (3,4-dihydroxy-3-acetamidopropyl-L-3- (3,4-dihydroxy-) hydroxide is obtained. EXAMPLE 4: Preparation of hydrochlorosiphenyl) -2-methylalaninate, K.0.5 (p-paloyloxymethyl-L-3- {tone 3.4-layer chromatography on silica gel, α-dihydroxyphenyl) -2-methylalaninate. : methanol: chloroform (1: 3). . A solution of 0.95 g (4.0 mol) L -3 Found,%: C 48.73; H 6.85; Mb, 68- (3,4-dihydroxyphenyl) -2-methylalanine
С,,Н,,.,0в виде, полуторного гидрата и 0.61 гC ,, H ,,., 0в, form, sesquiohydrate and 0.61 g
15 22 а 5 2 2 4- 22Р(54,06 ммол ) пивалоилоксиметилхлоВычислено ,%: С 48,80; Н 6,2€; рида в 5 мп диметилсульфоксида переме-15 22 a 5 2 2 4- 22P (54.06 mmol) pivaloyloxymethylchloride Calculated,%: C 48.80; H 6,2 €; 5 mp of dimethyl sulfoxide
N6,69. шивают при 20-25с 23 час. РастворN6.69. sew at 20-25 with 23 h. Solution
Т.пл. 95-98 С.разбавл ют 10 мл дистиллированной воПримерз . Получение кислогоды и пропускают через колонку, наполоксалата 2-метилтиоэтил- Ь-3-(3,4-ди- „ненную 5 г слабоосновной анионообменгидроксифенил )-2-метилаланината. смолы. После элюировани M.p. 95-98 C. diluted with 10 ml of distilled water. Preparation of acidic water is passed through a column, napoloxalate of 2-methylthioethyl-L-3- (3,4-di-nated 5 g of weakly basic anion exchange hydroxyphenyl) -2-methyl alaninate. resin. After elution
К 250 г полуторного гидрата Ц 3-объедин ют те фракции, которые пока- (3,4-дигидроксифенил)-2-метилаланиназывают положительную реакцию на пробу при добавл ют 275 мл хлористогохлоридом железа и пропускают через тионила, смесь нагревают на паровойколонку, наполненную 3 г слабокислотбане в течение двух часов, концентри,- 40ной катионообменной смолы. Непрореарованную реакционную смесь разбавл ютгировавший L -3-(3,4-дигидpoкcифeнил)7 ,5 мл диметилформамида, растворенно--2-метилаланин вымывают дистиллирого в 25 .мл бензола, и перемешивают ееванной водой до тех пор, пока не буна паровой бане до прекращени газо-дет достигнута отрицательна реакци выделени . Добавл ют 100 мл бензола, 45на хлорид железа, а затем сложный эфир сырой эфир сернистой кислоты отфильт.-элюируют 1 Н. уксусной кислотой. 50мл ровывают, промывают 100 мл бензола,эфирной фракции (рН 3,2), подкисл ют 100 мл хлороформа и 100 мл эфира иi н. сол ной кислотой до рН 2,0 и омы-, сушат при пониженном давлении, полу л ют 20 час при давлении о, 1-0,3мм. рхст., чают 280 г промежуточного сложного 50образуетс уксуснокислый сольват пи- : эфира сернистой кислоты, с т.пл. 199 Свалойлоксиметил- li -3-(3,4-дигидpoкcи (paзл.). .фенил)-2-метилаланин .гидрохлорида.To 250 g of a half hydrate of C 3, the fractions that until- (3,4-dihydroxyphenyl) -2-methylalanine are positive are challenged to a sample, 275 ml of ferric chloride are added and passed through thionyl, the mixture is heated to a steam column filled with 3 g mild acid bath for two hours, concentrate, - 40th cation exchange resin. Unprocessed reaction mixture diluted with L-3- (3,4-dihydroxyphenyl) 7, 5 ml of dimethylformamide diluted with 2-methyl-alanine, dissolved in 25 ml of benzene with distilled water, and stirred with this water until the bath bath stopping the gas, a negative release reaction was achieved. 100 ml of benzene, 45n ferric chloride, and then the crude ester of the sulfuric acid filter are added. - eluted with 1N acetic acid. 50 ml, washed with 100 ml of benzene, ethereal fraction (pH 3.2), acidified with 100 ml of chloroform and 100 ml of ether and n. hydrochloric acid to pH 2.0 and ohm-, dried under reduced pressure, was obtained 20 hours at a pressure of about 1-0.3 mm. Max., Some 280 g of the intermediate complex 50 is formed of acetic acid solvate of pi-: sulfurous acid ester, with m.p. 199 Svaloyloxymethyl-3- (3,4-dihydroxy (sol.). Phenyl) -2-methylalanine hydrochloride.
Смесь 30 г сырого сложного эфира Найдено,%s С 52.,И; Н 6,49Т N 3,73 сернистой кислоты, 34,6 г (0,375 мол ) С / ггИ+Оа 2-гидроксиэтилметилсульфида и 6 г Вычислено,%:: e.52,13f. Н 6,69; водного диметилформамида перемешивают N 3,58.A mixture of 30 g of crude ester Found,% s C 52., And; H 6.49T N 3.73 sulfurous acid, 34.6 g (0.375 mol) C / IHI + Oa 2-hydroxyethylmethyl sulfide and 6 g Calculated,% :: e.52,13f. H 6.69; aqueous dimethylformamide is stirred N 3,58.
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US40060973A | 1973-09-25 | 1973-09-25 | |
US05/482,102 US3983138A (en) | 1973-09-25 | 1974-06-25 | Amino acid esters |
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SU742063140A SU608471A3 (en) | 1973-09-25 | 1974-09-24 | Method of preparing a-methyl-3,4-dioxyphenylalanine derivatives or salts thereof |
SU762316005A SU620204A3 (en) | 1973-09-25 | 1976-01-27 | Method of obtaining a-methyl-3,4-dioxyphenylalanine derivatives or salts thereof |
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AR (1) | AR210248A1 (en) |
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DK (1) | DK478574A (en) |
EG (1) | EG11695A (en) |
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1974
- 1974-09-03 DD DD181243A patent/DD116454A5/xx unknown
- 1974-09-11 DK DK478574A patent/DK478574A/da not_active Application Discontinuation
- 1974-09-12 SE SE7411508A patent/SE421789B/en not_active IP Right Cessation
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- 1974-09-13 FI FI2680/74A patent/FI61687C/en active
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- 1974-09-23 BG BG027759A patent/BG25790A3/en unknown
- 1974-09-23 ES ES430320A patent/ES430320A1/en not_active Expired
- 1974-09-24 EG EG416/74A patent/EG11695A/en active
- 1974-09-24 SU SU742063140A patent/SU608471A3/en active
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1976
- 1976-01-27 SU SU762316005A patent/SU620204A3/en active
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1981
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IE40256L (en) | 1975-03-25 |
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CS200172B2 (en) | 1980-08-29 |
JPS58208256A (en) | 1983-12-03 |
YU37313B (en) | 1984-08-31 |
NO145690C (en) | 1982-05-12 |
ZM14074A1 (en) | 1976-11-22 |
BG25790A3 (en) | 1978-12-12 |
ES430320A1 (en) | 1977-02-16 |
IL45669A0 (en) | 1974-11-29 |
PH11794A (en) | 1978-07-05 |
YU37117B (en) | 1984-08-31 |
FI61687B (en) | 1982-05-31 |
NO743274L (en) | 1975-04-21 |
FI268074A (en) | 1975-03-26 |
NO145690B (en) | 1982-02-01 |
RO69156A (en) | 1981-11-24 |
HU171136B (en) | 1977-11-28 |
JPS632545B2 (en) | 1988-01-19 |
SE7411508L (en) | 1975-03-26 |
DD116454A5 (en) | 1975-11-20 |
SE421789B (en) | 1982-02-01 |
SU620204A3 (en) | 1978-08-15 |
EG11695A (en) | 1977-10-31 |
YU251474A (en) | 1982-06-18 |
YU50381A (en) | 1983-04-27 |
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IL45669A (en) | 1977-08-31 |
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